1. Field of the Invention
This invention relates to nerve tissue stimulation and infusion techniques, and more particularly relates to such techniques for treating schizophrenia.
2. Description of Related Art
The etiology of schizophrenia is unknown. Many hypotheses have been formulated including infectious (slow virus), genetic, autoimmune or immune dysfunction, environmental and neurotransmitter-mediated. Scans and postmortem studies show abnormalities in schizophrenics, such as enlarged cerebral ventricles and reduced brain size. Brain systems making use of dopamine appear to be particularly involved. Pet scans show that the prefrontal cortex of schizophrenic patients is not properly activated in response to intellectual tasks. Schizophrenia includes disturbances in one or more of three domains of psychopathology. Essentially all patients manifest "positive" symptoms that include delusions and hallucinations. A small majority also have thought disorders. A substantial minority are afflicted with primary, enduring negative symptoms such as flat affect, asociality, anhedonia and intentional impairment. The prevalence of schizophrenia in the U.S. is estimated to be 1.1 million persons with schizophrenia proper and another 2% to 3% of the population suffer schizotypal personality disorder which may simply be a mild form of the disorder. There is a genetic predisposition to schizophrenia. The odds for any person in the general population to suffer from the illness is 1%. The odds that a person will have the illness if they have a parent or sibling with schizophrenia is 15%. And if they have an identical twin with schizophrenia the odds are between 30% and 50% that they will also have it.
The cause of schizophrenia is unknown. However, there are several hypotheses that are described above. The structures of the brain that are involved in schizophrenia are suggested by the symptoms that become manifest during the phases of the illness and by the pharmaceutical agents that have an effect on those symptoms. The effectiveness of the neuroleptic drugs (typical antipsychotic) which block the dopamine as a transmitter has led to the hypothesis that schizophrenia is the result of dysfunction of neurons utilizing dopamine as a neurotransmitter. In particular, researchers believe that there is an overactivity in these circuits which utilize dopamine.
There are several circuits in the brain that utilize dopamine: the mesolimbic pathways; the nigrostrial pathway; the mesocortical dopaminergic system and the tuberoinfundibular dopaminergic system. There is a hypothesis that overactivity of dopaminergic neurons in one or more of these pathways leads to the symptoms observed in schizophrenia. The overactivity could be either an increase in dopamine release or a hypersensitivity of the receptors. Recent reformations of the hypothesis argue that there is both hyper and hypo dopaminergic activity in schizophrenia patients. The positive symptoms are probably due to increased activity in the mesolimbic dopamine pathways while the negative symptoms are the result of decreased activity in the mesocortical pathway. The hyperactivity may not be the same from side to side. For example, research has shown increased levels of dopamine in the left amygdala of persons with schizophrenia.
Recently, a new class of drug has been found to be effective for treating schizophrenia. This drug, clozapine, is referred to as an atypical antipsychotic. The typical antipsychotic drugs bind to the D2 dopamine receptor and give rise to extrapyramidal side effects through interactions in the nigrostriatal pathways. Clozapine, on the other hand, binds to D3 and D4 dopamine neurons and does not exhibit these side effects. Clozapine does cause systemic side effects in some cases and needs to be monitored closely for these effects.
There are other biochemical hypotheses that are put forward to explain schizophrenia. These hypotheses are motivated by the fact that researchers have had difficulty documenting the dopamine hypothesis, the failure of the antipsychotic drugs to always be effective and an understanding of the neurochemistry of other pathways that have been shown to be the substrate for many of the symptoms manifest by schizophrenic patients. Other neurotransmitters postulated to be involved include serotonin (5-HT), norepinepherine and the excitatory amino acids (glutamate).
Jaskiw and Weinberger (Seminars in The Neurosciences, Vol. 4, 1992: pp. 179-188) have emphasized the concept that it is a dysfunction of the prefrontal cortex which leads to the disregulation of the dopamine systems. In other words, the excess dopamine activity is secondary to the original problem that lies in the cortex. Drug therapy that alters the dopamine activity is a means of compensating the nervous system to regain some balance. Specifically, Weinburger postulates that it is the loss of input to the prefrontal cortex and the resulting lack of feedback to the other circuits in the limbic areas and the brainstem that lead to the hyperactivity of the dopamine limbic pathways.